Powder compositions for inhalation

ABSTRACT

The present invention relates to methods of making a powder for inhalation comprising a first step of mixing particles of a force-controlling agent selected from the group consisting of phospholipids, titanium dioxide, aluminum dioxide, silicon dioxide, starch, and salts of fatty acids, with particles of one or more pharmacologically active materials, wherein the mixing is achieved by one or more of the processes of sieving, mixing or blending, and wherein the mixing results in the particles of the force-controlling agent being disposed on the surface of the particles of the one or more pharmacologically active materials as either a particulate coating or as a continuous or discontinuous film.

The present invention is concerned with powder formulations for use indry powder inhalers (DPIs) and methods of forming such powderformulations.

Powder formulations typically consist of a binary mixture of small drugparticles having a mean aerodynamic diameter of about 1 to 10 microns,and a coarser carrier material for said drug particles. These componentsare usually blended together to form a so-called “interactive mixture”wherein the finer drug particles are strongly adhered to the carrierparticles. The use of interactive mixtures enables powders to be handledmore easily during manufacture and during filling of the powder into DPIdevices. Additionally, the small drug particles are maintained in arelatively dispersed state on the surface of the carrier particles.

When a DPI is actuated, the fine drug particles should detach from thecarrier particles in order that they can be inhaled deep into apatient's respiratory tract. Depending on the nature of the drugsubstance and the carrier material, the force of adhesion can be strongor weak. If the force of adhesion is too strong, the detachment of finedrug particles from carrier particles can be very low and the resultingfine particle fraction of the dose emitted from a DPI can be very low asto be ineffectual. Powder engineers have developed several means bywhich they may influence this force of adhesion in order to produceinteractive mixtures that possess a quality of adhesion that keeps theinteractive mixture together during handling and storage, but which uponactuation of a DPI is not so strong as to prevent the efficient andreproducible re-dispersion of the drug into fine inhalable particles.

One such means is the use of a ternary component in the mixture. Suchternary components are often referred to in the art as force controllingagents or anti-adherent additives. The use of such additives ininteractive mixtures is discussed in U.S. Pat. No. 6,521,260. Additivesmentioned therein include amino acids, e.g. leucine, isoleucine, lysine,valine, methionine, phenylalanine, and salts of derivatives thereof suchas aspartame or acesulfame K; peptides and polypeptides having molecularweight from 0.25 to 1000 KDa, and derivatives thereof; and phospholipidsor derivative thereof, e.g. lecithin, more particularly soya lecithin;talc; titanium dioxide; aluminium dioxide; silicon dioxide; and starch.

Other very useful force controlling agents are the salts of fatty acidssuch as lauric acid, palmitic acid, stearic acid, erucic acid, behenicacid, or derivatives (such as esters and salts) thereof. Specificexamples of such materials are: magnesium stearate; sodium stearylfumarate; sodium stearyl lactylate; phospatidylcholines,phosphatidylglycerols and other examples of natural and synthetic lungsurfactants; Liposomal formulations; lauric acid and its salts, forexample, sodium lauryl sulphate, magnesium lauryl sulphate;triglycerides such as Dynsan 118 and Cutina HR; and sugar esters ingeneral.

A particularly useful additive has been found to be magnesium stearate.The use of magnesium stearate in interactive mixtures is the subject ofU.S. Pat. No. 6,645,466.

Interactive mixtures are usually formed by mixing or blending processes.A typical procedure consists of mixing a micronised drug substance witha powdered carrier material. Usually, the carrier material ispre-treated, for example the powder may be pre-blended in order tochange its surface structure and therefore its surface energy in anattempt to manipulate the adhesion forces. When a ternary component isused, it is typical to treat the carrier with it, once again in order toinfluence the surface energy of the carrier particles.

The benefit of using magnesium stearate in dry powders is taught in U.S.Pat. No. 6,528,096. Specifically it teaches that it can be used to alterthe surface properties of carrier particles and thereby improve theproperties of dry powder formulations. This reference reports an“advantageous relationship” between surface coating carrier particleswith magnesium stearate and the respirable fraction (fine particlefraction) of the emitted dose. Critical to the working of this inventionis the need to ensure a continuous coating of magnesium stearate overmore than 10% of the surface of the carrier particles. The requisitecoating can be achieved by conventional blending of carrier andmagnesium stearate, or alternatively mixing techniques applying highershear forces can be employed. High shear mixing can achieve therequisite coating within about 0.5 hour, however, the skilled person isclearly taught that if conventional blending is to be employed theblending time must be in excess of 2 hours. In The Journal of AerosolMedicine Vol 11, No. 3, 1998 at 143-152, an inventor of U.S. Pat. No.6,528,096 teaches that pre-treatment of lactose particles with 0.25%magnesium stearate significantly improves the de-aggregation ofbeclamethasone dipropionate without causing segregation, i.e. separationof drug and carrier particles, during filling, transport or use.

In Pharmaceutical Research Vol 14, No 11 (Supplement), 1997 at pagesS-142-S-143, the authors of whom one is an inventor of U.S. Pat. No.6,528,096 teach that magnesium stearate was found to be an effectivede-stabilizer by the proposed mechanism of reducing the electrostaticattraction force.

It is clear from the prior art that any beneficial properties thatderive from the use of magnesium stearate are predicated on it coatingcarrier particles to some degree and thereby altering the surfaceproperties of the particles. In this regard, the skilled person istaught that in order to advantageously influence the fine particlefraction of an emitted dose, the carrier particles should obtain acontinuous or discontinuous surface coating of magnesium stearate.Certain mixing techniques are taught for achieving this result, whichinvolve either high energy mixing, or long duration low energy mixing ofmagnesium stearates and carrier material. Other suggestions involvecombining low energy blending coupled with carrier treatment stepsinvolving high energy milling or mixing. Finally, Wagner et al inPharmazie 60, 339-344 (2005) in studying the adhesion phenomena ofinteractive mixtures noted that the energetics of drug-to-carrierinteractions are favourable compared to drug-to-drug interactions. Thisis rationalized on the basis that the fine drug particle sphere hasgreater contact with the surface of a much larger carrier particle(essentially sphere-to-plate contact) compared to the sphere-spherecontact of adjacent drug particles. Indeed, he reports that in fact, nodrug-drug agglomerates were observed in the mixtures studied.

In summary, the prior art recognizes the problem of adhesion ininteractive mixtures and suggests that the surface properties of thecarrier material should be modified either mechanically or chemically bycoating or partially coating with a ternary component. Nowhere is therea suggestion in the art to modify the surface properties of fine drugparticles. Indeed, drug-drug interactions appear to be energeticallyunfavourable relatively speaking and it is perhaps not surprising thatthe art is concerned with treating carrier particles rather thantreating the surface properties of drug particles. However, applicanthas found that surface coating carrier particles with a ternarycomponent does not always assure good blend homogeneity in interactivemixtures.

Applicant has now surprisingly found that powder formulations consistingof interactive mixtures of fine drug particles and carrier particles canbe obtained if the fine drug particles are pre-treated with aforce-controlling agent before blending with carrier particles to forman interactive mixture.

Accordingly, in a first aspect of the present invention there isprovided a pharmacological powder for inhalation comprising fine drugparticles and optionally carrier particles for supporting said drugparticles, the formulation further containing a force-controlling agent,wherein the force-controlling agent is disposed on the surface of thefine drug particles as either a particulate coating, or as a continuousor discontinuous film.

The force-controlling agent of the present invention may be any materialknown for this purpose in the art. U.S. Pat. No. 6,521,260 disclosescertain so-called force-controlling agents or anti-adherent additivesthat are useful in the present invention. These additives may beselected from amino acids, e.g. leucine, isoleucine, lysine, valine,methionine, phenylalanine, and salts of derivatives thereof such asaspartame or acesulfame K; peptides and polypeptides having molecularweight from 0.25 to 1000 KDa, and derivatives thereof; and phospholipidsor derivative thereof, e.g. lecithin, more particularly soya lecithin;talc; titanium dioxide; aluminium dioxide; silicon dioxide; and starch.

However, preferred force-controlling agents are the salts of fatty acidssuch as lauric acid, palmitic acid, stearic acid, crude acid, behenicacid, or derivatives (such as esters and salts) thereof. Specificexamples of such materials are: magnesium stearate; sodium stearylfumarate; sodium stearyl lactylate; phospatidylcholines,phosphatidylglycerols and other examples of natural and synthetic lungsurfactants; Liposomal formulations; lauric acid and its salts, forexample, sodium lauryl sulphate, magnesium lauryl sulphate;triglycerides such as Dynsan 118 and Cutina HR; and sugar esters ingeneral.

A more preferred force-controlling agent for use in compositions of thepresent invention is magnesium stearate. The amount of force-controllingagent employed should be at large enough to reduce the auto-adhesionforce present between the drug particles. The upper limit depends on thetoxicological acceptability of large amounts of force-controlling agentdelivered to the lungs. A level of up to 2.0% is preferred. Within theselimits, the amount of force-controlling agent employed will depend onthe nature of the drug, and the drug loading. The skilled person willhave regard the physical and chemical properties of the drug and be ableto select an appropriate amount without undue burden or without havingto resort to inventive activity.

In a particular embodiment a force-controlling agent, more particularlymagnesium stearate may be employed in an amount of 0.01 to 2.0% byweight, more particularly 0.1 to 1.5% by weight, still more particularly0.25 to 1.0% by weight, even more particularly 0.5 to 1.0% by weight.The fine drug particles covered by force-controlling agent particles ora film can be used per se since the auto-adhesion forces between drugparticles can be largely reduced. However, if the bulk powder propertiesof any drug/force-controlling agent mixture are inappropriate for use ina dry powder inhaler, the mixture may be further formulated to asuitable powder composition by methods known to the skilled person fromthe prior art. The resulting powder for inhalation may be in form of apelletized formulation or of an ordered mixture by adding a carriermaterial. The carrier material may be any carrier material thatcustomarily finds use in dry powder formulations. As examples thereof,one can mention mono- or di-saccharides such as glucose, glucosemono-hydrate, lactose, lactose mono-hydrate, sucrose or trehalose; sugaralcohols such as mannitol or xylitol; polylactic acid or cyclodextrin;or mixtures thereof. Preferably lactose mono-hydrate is employed.

Any drug substance may be employed in a formulation according to thepresent invention. The force-controlling agent is employed in the mannerdescribed as means of disrupting inter-particulate forces between drugparticles, and promoting the adhesion of drug particles to carrierparticles thereby to form the desired interactive mixtures.

There are different types of inter-particulate forces present in bulkpowders and their absolute size and relative contribution depend on thesurface chemistry and physical characteristics of the particles in thebulk. A general description is given for example in F. Podczeck“Particle-particle Adhesion in Pharmaceutical Powder Handling”, ImperialCollege Press, London 1998, pages 4-15. Hydrophilic interactions arelarger than hydrophobic interactions and thus hydrophilic materials areless easy to disperse. This is owing to the capillary force that isgenerated due to interstitial moisture condensation between contiguousparticles, which may be in evidence at ambient air relative humidityvalues of about 50%. In addition, porous hydrophilic particles oftencontain moisture trapped in pores. The capillary force generated by thismechanism is about 10 times stronger than other inter-particulateforces. Between particles of hydrophobic character, capillary forces areless in evidence, which means that strong inter-particulate especiallypresent in hydrophilic compounds are generally not an issue forhydrophobic particles.

Also below a relative humidity value for ambient air of about 50%hydrophilic particles may show increased inter-particle adhesion becauseof absorbed moisture acting as a plasticizer. The plasticizing effectresults in an increased contact area of the particles and therefore anincreased Lifshitz-van der Waals inter-particulate force. From the aboveit is clear to one skilled in the art that drugs, which consist of softhydrophilic particles are even more likely to be affected because thetrue area of contact between the particles may easily increase duringstorage and normal handling operations of bulk powder.

Hydrophilicity is the tendency of a compound to be solvated by water.More generally, hydrophilic compounds tend to adsorb readily water priorto solvation. The surface chemistry allows such compounds to be wettedreadily, and particles of such compounds can form surface water films orlayers. Hydrophilic materials are characterized by the fact that theypossess a high surface tension value and have the ability to formhydrogen-bonds. There are many parameters that serve to definehydrophilic compounds. One such parameter is the octanol-water partitioncoefficient. Hydrophilic compounds have low values for this coefficient.In particular, hydrophilic drugs may be characterized for the purpose ofthe present invention as having a decadic logarithm of the octanol-waterpartition coefficient (Log P) smaller than 2, more particularly smallerthan 1, even more particularly smaller than 0.5.

Another method of characterizing a hydrophilic drug is by measuring itscontact angle against water. In particular, hydrophilic drugs for thepurpose of the present invention may be characterized by a water contactangle smaller than 90°, more particularly smaller than 80°, even moreparticularly smaller than 70°.

Notwithstanding the generality of the present invention, having regardto the foregoing, the present invention is particularly advantageouswhen employed in the formulation of hydrophilic drugs.

The following drug substances in particular can be employed informulations of the present invention:

Active substances may be chosen from beta-mimetics such as Levalbuterol,Terbutalin, Reproterol, Salbutamol, Salmeterol, Formoterol, Fenoterol,Clenbuterol, Bambuterol, Tulobuterol, Broxaterol, Indacaterol,Epinephrin, Isoprenaline or Hexoprenaline; an Anticholinergic such asTiotropium, Ipratropium, Oxitropium or Glycopyrronium; a Corticosteroid,such as Butixocart, Rofleponide, Budesonide, Ciclesonide, Mometasone,Fluticasone, Beclomethasone, Loteprednol or Triamcinolone; aLeukotrienantagonist, such as Andolast, Iralukast, Pranlukast,Imitrodast, Seratrodast, Zileuton, Zafirlukast or Montelukast; aPhosphodiesterase-Inhibitor, such as Filaminast or Piclamilast; anPAF-Inhibitor, such as Apafant, Forapafant or Israpafant; a potassiumchannel opener such as Amiloride or Furosemide; a pain killer such asMorphine, Fentanyl, Pentazocine, Buprenorphine, Pethidine, Tilidine,Methadone or Heroin; a potency agent such as Sildenafil, Alprostadil orPhentolamine; or a pharmaceutically acceptable derivative or salt of anyof the foregoing compounds or classes of compounds. In as much as any ofthese compounds possess chiral centres, the compounds can be used inoptically pure form, or can be presented as diastereomeric mixtures orracemic mixtures. Dry powders of the present invention may also employproteins, peptides, oligopeptides, polypeptides, polyamino acids nucleicacid, polynucleotides, oligo-nucleotides and high molecular weightpolysaccharides. Examples of macromolecules that find use in the presentinvention are: —Albumins (preferably, human serum Insulin; albumin);BSA; IgG; IgM; insulin; GCSF; GMCSF; LHRH; VEGF; hGH; lysozyme;alpha-lactoglobulin; basic fibroblast growth factor basic fibroblastgrowth factor; (bFGF); asparaginase; tPA; urokinase-VEGF; chymotrypsin;trypsin; streptokinase; interferon; carbonic anhydrase; ovalbumin;glucagon; ACTH; oxytocin; phosphorylase b; alkalinephosphatase-secretin; vasopressin; levothyroxin; phatase;beta-galactosidase; parathyroid hormone, calcitonin; fibrinogen;polyaminoacids (e.g., DNAse, alphal antitrypsin; polylysine,polyarginine); angiogenesis inhibitors or pro-immunoglobulins (e.g.,antibodies); moters; somatostatin and analogs; casein; collagen;gelatin; soy protein; and cytokines (e.g., interferon, interleukin);immunoglobulins;

Physiologically active proteins such as peptide hormones, cytokines,growth factors, factors acting on the cardiovascular system, factorsacting on the central and peripheral nervous systems, factors acting onhumoral electrolytes and hemal substances, factors acting on bone andskeleton, factors acting on the gastrointestinal system, factors actingon the immune system, factors acting on the respiratory system, factorsacting on the genital organs, and enzymes;

Hormones and hormone modulators including insulin, proinsulin, C-peptideof insulin, a mixture of insulin and C-peptide of insulin, hybridinsulin cocrystals (Nature Biotechnology, 20, 800-804, 2002), growthhormone, parathyroid hormone, luteinizing hormone-releasing hormone(LH-RH), adrenocorticotropic hormone (ACTH), amylin, oxytocin,luteinizing hormone, (D-Tryp6)-LHRH, nafarelin acetate, leuprolideacetate, follicle stimulating hormone, glucagon, prostaglandins,estradiols, testosterone, and other factors acting on the genital organsand their derivatives, analogues and congeners. As analogues of saidLH-RH, such known substances as those described in U.S. Pat. Nos.4,008,209, 4,086,219, 4,124,577, 4,317,815 and 5,110,904 can bementioned;

Hematopoietic or thrombopoietic factors include, among others,erythropoietin, granulocyte colony stimulating factor (G-CSF),granulocyte-macrophage stimulating factor (GM-CSF) and macrophage colonystimulating factor (M-CSF), leukocyte proliferation factor preparation(Leucoprol, Morinaga Milk), thrombopoietin, platelet proliferationstimulating factor, megakaryocyte proliferation (stimulating) factor,and factor VIII;

Therapeutic factors acting on bone and skeleton and agents for treatingosteoporosis including bone GLa peptide, parathyroid hormone and itsactive fragments (osteostatin, Endocrinology 129, 324, 1991), histoneH4-related bone formation and proliferation peptide (OGP, The EMBOJournal 11, 1867, 1992) and their muteins, derivatives and analogsthereof;

Enzymes and enzyme cofactors including pancrease, L-asparaginase,hyaluronidase, chymotrypsin, trypsin, tPA, streptokinase, urokinase,pancreatin, collagenase, trypsinogen, chymotrypsinogen, plasminogen,streptokinase, adenyl cyclase, and superoxide dismutase (SOD);

Vaccines include Hepatitis B, MMR (measles, mumps, and rubella), andPolio vaccines;

Growth factors include nerve growth factors (NGF, NGF-2/NT-3), epidermalgrowth factor (EGF), fibroblast growth factor (FGF), insulin-like growthfactor (IGF), transforming growth factor (TGF), platelet-derived cellgrowth factor (PDGF), and hepatocyte growth factor (HGF);

Factors acting on the cardiovascular system including factors whichcontrol blood pressure, arteriosclerosis, etc., such as endothelins,endothelin inhibitors, endothelin antagonists described in EP 436189,457195, 496452 and 528312, JP [Laid Open] No. H-3-94692/1991 and130299/1991, endothelin producing enzyme inhibitors vasopressin, renin,angiotensin I, angiotensin II, angiotensin III, angiotensin I inhibitor,angiotensin II receptor antagonist, atrial naturiuretic peptide (ANP),and antiarrythmic peptide; Factors acting on the central and peripheralnervous systems including opioid peptides (e.g. enkephalins,endorphins), neurotropic factor (NTF), calcitonin gene-related peptide(CGRP), thyroid hormone releasing hormone (TRH), salts and derivativesof TRH [JP [Laid Open]No. 50-121273/1975 (U.S. Pat. No. 3,959,247), JP[Laid Open]No. 52-116465/1977 (U.S. Pat. No. 4,100,152)], andneurotensin;

Factors acting on the gastrointestinal system including secretin andgastrin;

Factors acting on humoral electrolytes and hemal substances includingfactors which control hemagglutination, plasma cholesterol level ormetal ion concentrations, such as calcitonin, apoprotein E and hirudin.Laminin and intercellular adhesion molecule 1 (ICAM 1) representexemplary cell adhesion factors;

Factors acting on the kidney and urinary tract including substanceswhich regulate the function of the kidney, such as brain-derivednatriuretic peptide (BNP), and urotensin;

Factors which act on the sense organs including factors which controlthe sensitivity of the various organs, such as substance P;

Chemotherapeutic agents, such as paclitaxel, mytomycin C, BCNU, anddoxorubicin;

Factors acting on the immune system including factors which controlinflammation and malignant neoplasms and factors which attack infectivemicroorganisms, such as chemotactic peptides and bradykinins; and

Naturally occurring, chemically synthesized or recombinant peptides orproteins which may act as antigens, such as cedar pollen and ragweedpollen, and these materials alone or together with coupled to haptens,or together with an adjuvant.

The present invention is particularly useful in the formulation ofhydrophilic and moisture sensitive active substances, such as the saltforms of any of the compounds mentioned above such as the chloride,bromide, iodide, nitrate, carbonate, sulphate, methylsulphate,phosphate, acetate, benzoate, benzensulphonate, fumarate, malonate,tartrate, succinate, citrate, lactate, gluconate, glutamate, edentate,mesylate, pamoate, pantothenate or hydroxynaphthoate; or an ester formsuch as an acetate, propionate, phosphate, succinate or etabonate.

Formulations containing a beta-mimetic, an anti-cholinergic or acorticosteroid, alone or in any combination thereof constitute preferredembodiments of the present invention. These actives may be present insalt or ester form, such as a beta-mimetic in salt form, e.g.levalbuterol sulphate, formoterol fumarate, formoterol tartrate,salbutamol sulphate or salmeterol xinafoate (salmeterol1-hydroxy-2-naphthoate); or a corticosteroid in the form of an ester,such as beclamethasone dipropionate, fluticasone propionate,triamcinoline 16,21-diacetate, triamcinoline acetonide 21-acetate,triamcinoline acetonide 21-disodium phosphate, triamcinoline acetonide21-hemisuccinate, mometasone furoate, or loteprednol etabonate.

In a most preferred embodiment of the present invention the formulationcontains an anti-cholinergic agent in salt form such as oxitropiumbromide, glycopyrronium bromide (glycopyrrolate), ipratropium bromide ortiotropium bromide.

In another aspect of the present invention there is provided a method oftreating a medical condition comprising administering to a patient inneed thereof a pharmacological powder of the present invention. Saidpowder may suitably be administered to parenterally to an human patient,in particular by inhalation, using, for example, a DPI.

A method of formulating powder formulations hereinabove described formsyet another aspect of the present invention.

The formulations of the present invention may be prepared in such amanner that the drug is first brought in contact with the appropriateamount of force-controlling agent. Close contact of particles offorce-controlling agent with drug particles is necessary and importantto achieve a reduction of the auto-adhesion forces established in thebulk drug powder. The close contact can be achieved by methods known tothe skilled person. Particularly, screening both drug and agent througha narrow sieve gives a neat dispersion of both particle populations.Appropriately sized sieves for this operation are e.g. 25 to 250micrometer size (500 to 60 mesh according to BS 410), more particularly25 to 180 micrometer (500 to 85 mesh according to BS 410), even moreparticularly 25 to 90 micrometer (500 to 170 mesh according to BS 410).

Additionally or alternatively, blending and mixing apparatus may beapplied to achieve close inter-particle contact, for example tumbleblenders, bin blenders, conical blenders and the like. High shear mixerscan also be used if the auto-adhesive properties of the drug particlesare so that high shear forces are required together with use of aforce-controlling agent for forming a surface-energy-reducingparticulate coating or film. Particularly, tumble blending may beapplied for this purpose.

If the fine drug particles to be formulated as a powder formulation forinhalation are not of the appropriate size suitable for the inhaledroute, particle reduction techniques in the presence offorce-controlling agent can be applied to yield particles of suitablesize. The preferred method is co-micronisation using an air jet millwhich again brings the drug particles and the particles offorce-controlling agent in such a contact that either a continuous ordiscontinuous film is formed or the agent particles adhere to the drugparticle surface. However, any technique known in the art and suitablefor co-micronisation can be employed.

Accordingly, the invention provides in another of its aspects a methodof producing powder formulations containing fine drug particlescomprising the step of blending one or more pharmacologically activecompound with a force-controlling agent in a powder blender. In yetanother aspect of the present invention there is provided a method ofproducing powder formulations containing fine drug particles comprisingthe step of co-micronising one or more pharmacologically active compoundwith a force-controlling agent. Preferred powder blenders includediffusion blenders and tumble blenders.

The blending step described above is preferably carried out as one of aseries of blending steps described below.

In a first step, one or more drugs and force-controlling agent are mixedtogether in such a way that the agent adheres to the surface of the drugparticles either as a particulate coating or as a continuous ordiscontinuous film. As stated hereinabove, the treated drug particlesmay possess appropriate properties that enable them to be used alone ina dry powder inhaler device. However, if desired they may be furthermixed with a carrier material.

Accordingly, in an optional step the treated fine drug particles aremixed with a carrier material. This mixing step is preferably carriedout in a powder blender for a period not exceeding one hour andpreferably less than 30 minutes, more particularly less than 20 minutes,for example about 15 to 20 minutes.

The carrier material may be used untreated or it may be treated in thesame manner as the fine drug particles.

In the methods of the present invention, the drug, force-controllingagent and carrier material can be as stated already herein above.

If the amount of drug used in the formulation is low, e.g. less thanabout 30% by weight of the formulation, more particularly about 1% to20% by weight, even more particularly about 0.01 to 10% by weight of theformulation, it is preferred that after the treatment of the fine drugparticles, the resulting drug/force-controlling agent mixture is blendedwith a small portion of the carrier material, e.g. about 10%, to form apowder mixture relatively concentrated with respect to the drug. This isto ensure adequate mixing of the drug with the carrier material.Subsequently, an additional step is employed to mix the remainingcarrier material with the concentrated mixture from the earlier step.Again, this is preferably carried out in a powder blender. It ispreferred that no other blending step is carried out. However, it may bedeemed necessary to perform additional blending and sieving steps toachieve a final powder formulation of suitable quality.

To ensure the powder ingredients are of the appropriate particle size itis customary to prepare the ingredients by screening through appropriatesized sieves, e.g. 25 to 500 micrometer size (500 to 30 mesh accordingto BS 410), more particularly 63 to 250 micrometer (240 to 60 meshaccording to BS 410).

In order that the fine drug particles are inhalable, i.e. in order thatthey can pass into the deep lung such as the terminal and respiratorybronchioles and the alveolar ducts and sacs, they must be in particulateform having a mean particle diameter (measured as the mass meanaerodynamic diameter) of at most about 10 micrometers, e.g. from 1 to 10micrometers, and preferably 1 to 6 micrometers, even more preferably 1to 4 micrometers. Such micro-fine particles can be obtained in a mannerknown per se, for example by micronisation, controlled precipitationfrom selected solvents, or by spray drying.

The amount of drug employed may vary within wide limits depending on thenature of the drug, the type and severity of the condition to be treatedand the condition of the patient in need of treatment.

For drugs employed to treat local conditions of the lung such as allmanner of asthma and chronic obstructive pulmonary disease, relativelylow doses of drug can be employed, for example about 5 to 5000micrograms, more particularly 5 to 500 micrograms. For drugs that areintended to be delivered systemically through the lung, one may needhigher doses to take into account issues relating to absorption throughthe lung and into the blood plasma. Typically, one might employ drugs atlevels of about 20 micrograms to 50 milligrams, more particularly 50micrograms to 20 milligrams.

Expressed as a concentration based on the total weight of theformulation, the drug may be present in amounts of 0.01 to 30% byweight, more particularly 0.1 to 10% by weight, more particularly 0.1 to5% by weight. It is not surprising therefore that to achieve dosageaccuracy, the drug must be diluted with carrier material. In a typicalformulation the carrier material may be present in amounts of up to 99%by weight or more, in particular 50 to 99% by weight, depending on theparticular dilution desired and on the amount of force-controlling agentemployed in the formulation. The dilution is chosen such that anacceptable shot weight delivered from an inhaler contains exactly thedesired dose of drug. In this regard, the exact dose may be delivered ina single shot or multiple shots. Dilution is also used to affect powdermixtures having good macroscopic properties such as flowability, and tobalance adhesive or cohesive forces of the micro-fine active substanceto ensure good homogeneity of the formulation.

Nucleic acids, including double-stranded or single-strandedpolynucleotide, oligonucleotide or short nucleic acid sequences may alsobe formulated according to the present invention. The term nucleic acidincludes both RNA (e.g. siRNA, mRNA, ribozymes, aptamers) and DNA (e.g.cDNA or genomic DNA). The nucleic acid may be present in the form of avector (e.g. a plasmid or other construct) with suitable sequences todirect or control expression (i.e. a promoter sequence).

Carrier materials employed must be in the form of sufficiently largeparticle size such that they can be easily handled during manufactureand filling operations. They should also be large enough such that theyare not inhalable into the deep lung. Typically a carrier material willhave a mean particle diameter (measured as the mass mean aerodynamicdiameter) of about 10 to 500 micrometers, and preferably 50 to 300micrometers.

Dry powder formulations of the present invention are particularlysuitable for use in multi-dose dry powder inhalers. In particular, theformulations are suitable for use in such inhalers, which comprise areservoir from which individual therapeutic dosages can be withdrawn ondemand through actuation of the device. However, formulations of thepresent invention are also useful in multi-dose inhalers that contain aplurality of capsules containing single or multiple pre-dosed units.

Typical of such multi-dose inhaler device suitable for use withformulations of the present invention is described in U.S. Pat. No.6,182,655, which is hereby incorporated by reference in its entirety.

In yet another aspect of the present invention there is provided amethod of treating a medical condition comprising administering to apatient in need thereof a pharmacological powder made in accordance withthe method of the invention.

The present invention in another of its aspects is directed to suchmulti-dose inhalers containing the formulation of the present invention.

Multi-dose inhalers may contain a reservoir of dry powder that containstens or even hundreds of therapeutic doses. The term “therapeuticdose(s)” as used herein means an amount of inhalation formulationcontaining a requisite amount of drug to illicit a therapeutic effect,e.g. to alleviate, prevent or inhibit the particular condition to betreated, when delivered to a patient. A therapeutic dose may bedelivered with one or more actuations of a DPI device. This is becausethe amount of powder that can be delivered to a patient withoutirritating the patient, e.g. making the patient cough, or what canreasonably or comfortably be delivered within a single inspiration, islimited to about 50 mg per actuation, more particularly 25 mg peractuation. Accordingly, depending on the nature of the drug and thenature and severity of the condition to be treated, one or moreactuations may be necessary per number of hours, per day, for any numberof days, weeks, months and so-forth.

The therapeutic dose will depend largely on the nature of the drug, thecondition of the patient, and the nature and severity of the conditionto be treated. A therapeutic dose may range between as little as 1ng/kg, for example when treating a local condition such as asthma with apotent active substance to as much as 10 mg/kg, more particularly dosewill range from 20 ng/kg to 1 mg/kg. The therapeutic dose will beindicated on packaging or labelling accompanying the DPI device and isspecifically referred to in the Label Claim.

In order to ensure inter-batch quality and reproducibility, formulationsshould be tested in order to ensure that the mean dose of formulationemitted from a MDI, should not vary considerably from the Label Claim.In this regard, the formulations of the present invention areparticularly stable, for example they meet the following standards:

The Mean Delivered Dose is within +/−15% of the Label Claim, and 9 from10 at least of single doses are not outside +/−25% of the mean, and allsingle doses are within +/−35% of the mean; or

At least 9 from 10 single doses are within +/−20% of the Label Claim,and all single doses are within +/−25% of the Label Claim.

The Shot Weight and Delivered Dose and their variance can be measuredusing the Dosage Unit Sampling Apparatus (DUSA). The fine particlefraction (FPF) can be measured using an Andersen Cascade Impactor (ACI).The measurement methodology and the apparatus therefore are well knownin the art, and are described in the United States Pharmacopoeia Chapter<601>, or in the inhalants monograph of the European Pharmacopoeia, bothof which documents are hereby incorporated by reference. The USP statesthat the Apparatus 1 should be used for the measurement of FPF. The USPalso states that Delivered Dose Uniformity should be measured with DUSAor its equivalent. However, the Delivered Dose and Delivered Doseuniformity are preferably measured using the so-called Funnel Method.The Funnel Method is described in Drug Delivery to the Lungs, VIII p 116to 119, which is hereby incorporated by reference. In summary, theFunnel Method consists of discharging a formulation from a DPI into aFunnel Apparatus, which basically consists of a standard Buchner Funnel.The discharged dose is captured on the glass sinter of the Funnel, andcan be washed off, and the dose determined using HPLC analysis. TheFunnel Method gives comparable results to the standard USP apparatus,and is generally considered to be an equivalent of the DUSA apparatus.Fine particle fraction measured according to the above describedmethodology is considered to consist of the combined fractions collectedfrom stages 2 to Filter Stage of an Andersen Cascade Impactor calibratedat 60 L/min air flow rate. These fractions have an aerodynamic particlesize of less than 3.2 micrometers.

Alternatively, Fine Particle Fraction can be measured by the TwinImpinger Method and the Multi-stage Liquid Impinger Method as aredescribed in the Pharmacopoeia, and as are set forth in the Examplesbelow.

Formulations of the present invention meet pharmacopoeia requirements asto Delivered Dose Uniformity as set forth, for example in the UnitedStates and European Pharmacopoeias. For example, formulations of thepresent invention meet the requirement set out in the USP26-NF21 chapter<601> “Delivered Dose Uniformity”. Indeed, the formulations appear to beso stable that they may even meet the relatively more stringentDelivered Dose Uniformity requirements set forth in the current DraftGuidance from the FDA, published by the CDER in October 1998. Stillfurther, the Delivered Dose of the formulations contains a high fractionof fine particles, i.e. particles that are capable of penetrating thedeep lung, e.g. having a diameter of less than about 4.7 micrometers, asmeasured by the ACI; below 6.4 as measured by the Twin Impinger; andbelow 6.8 as measured by the Multi-stage Liquid Impinger.

There now follows a series of examples that serve to illustrate theinvention.

Method Particle Fraction Size Measurement Method

Assemble the Andersen Cascade Impactor according to manufacturer'sinstructions with a suitable filter in place and ensure that the systemis airtight. To ensure efficient particle capture, coat each plate witha high viscosity liquid deposited from a volatile solvent. Thepre-separator should be coated in the same way or should contain 10 mlof a suitable solvent. Connect the apparatus to a flow system comprisingflow control valve, two-way valve, timer and vacuum pump.

The test is conducted at a flow rate adapted to the internal resistanceof the inhaler device drawing 4 liters of air through the apparatus. Athigh flow rates it may be necessary to remove the lowest stages from thestack. For adjustment of the flow rate connect a flow meter, calibratedfor the volumetric flow leaving the meter, to the induction port. Adjustthe flow control valve to achieve steady flow through the system at therequired rate.

Ensure that critical flow occurs in the flow control valve by measuringthe absolute pressure on both sides of the flow control valve. Switchoff the airflow.

Prepare the dry-powder inhaler for use according to the patientinstructions. With the pump running and the two-way valve closed, locatethe mouthpiece of the inhaler in the mouthpiece adapter. Discharge thepowder into the apparatus by opening the valve for the time required fordrawing 4 liters of air through. Repeat the discharge sequence. Thenumber of discharges should be minimised and typically would not begreater than ten. The number of discharges should be sufficient toensure an accurate and precise determination of fine particle dose.After the final discharge, wait for 5 seconds and then switch off thepump.

Dismantle the apparatus. Carefully remove the filter and extract theactive ingredient into an aliquot of the solvent. Remove thepre-separator, induction port and mouthpiece adapter from the apparatusand extract the drug into an aliquot of the solvent. Extract the activeingredient from the inner walls and the collection plate of each of thestages of the apparatus into aliquots of solvent. Using a suitablemethod of analysis, determine the quantity of drug contained in each ofthe nine volumes of solvent.

Calculate the mass of drug deposited on each stage per discharge and themass of drug per discharge deposited in the induction port, mouthpieceadapter and where used the pre-separator. The total mass of the drug isnot less than 75 per cent and not more than 125 per cent of the averagedelivered dose determined during testing for uniformity of delivereddose. If the total mass is outside this range the test must be repeated.

Starting at the filter, derive a cumulative mass vs. cut-off diameter ofthe respective stages. Calculate the Fine Particle Dose (FPD) byinterpolation the mass of drug less than 5 μm. If necessary, and whereappropriate, plot the cumulative fraction of drug versus cut-offdiameter on log probability paper, and use this plot to determine valuesfor the Mass Median Aerodynamic Diameter (MMAD) and the GeometricStandard Deviation (GSD).

EXAMPLE 1 Formulation 1

A powder formulation consisting of glycopyrrolate (glycopyrroniumbromide), magnesium stearate and lactose monohydrate is formed asfollows: Glycopyrrolate and magnesium stearate are screened through a 38micrometer sieve. Lactose monohydrate is screened through a 250micrometer sieve. The sieved glycopyrrolate-magnesium stearate bulkpowder is mixed with about half the amount of sieved lactose monohydratein a Turbula T2C powder blender at 22 rpm for 10 minutes.

The resulting concentrated mixture is sieved through a 250 micrometersieve, the remaining lactose monohydrate is added and the mixtureblended for a further 10 minutes at 22 rpm in the blender.

The dry powder blend achieved is homogeneous when assessed visually andunder the microscope. The blend has satisfying blend homogeneity with arelative standard deviation of the drug content of the withdrawn samplesbelow 5%, usually even below 3%.

Formulation 2 For Comparison, Not Part of the Invention

A dry powder formulation consisting of glycopyrrolate (glycopyrroniumbromide), magnesium stearate and lactose monohydrate is formed accordingto a prior art process as follows: Lactose monohydrate and magnesiumstearate are screened through a 250 micrometer sieve and mixed in aTurbula T2C powder blender at 30 rpm for 20 minutes.

Glycopyrrolate and about half of the lactose-magnesium stearate mixtureare screened through a 250 micrometer sieve and mixed in a Turbula T2Cpowder blender at 46 rpm for 20 minutes.

Eventually, the resulting concentrated mixture and the remaining lactosemonohydrate are sieved through a 250 micrometer sieve and the mixtureblended for a 10 minutes at 46 rpm in the blender.

The dry powder blend achieved has an inhomogeneous aspect when assessedvisually and under the microscope. The blend homogeneity test gives arelative standard deviation of the drug content of the withdrawn samplesof more than 5%.

EXAMPLE 2 Formulation 3

A dry powder formulation consisting of glycopyrrolate (glycopyrroniumbromide), magnesium stearate and lactose monohydrate is formed accordingto the following method: Glycopyrrolate and magnesium stearate arescreened through a 38 micrometer sieve. Lactose monohydrate is screenedthrough a 250 micrometer sieve. Both sieved bulk powders are mixed in ahigh shear mixer Niro PP1 for 10 minutes at 300 rpm impeller speed and300 rpm chopper speed.

The powder blend achieved is homogeneous when assessed visually andunder the microscope. The blend has satisfying blend homogeneity with arelative standard deviation of the drug content of the withdrawn samplesbelow 5%, usually even below 3%.

EXAMPLE 3 Measurement of Fine Particle Fraction

The formulations 1 and 2 employed are those formed according to Example1 above. The powder blends thus produced are filled into SkyePharmaproprietary dry powder inhalers Skyehaler™ as more fully described inU.S. Pat. No. 6,182,655 for assessment of Dose Content Uniformity andfine particle fraction of the delivered dose.

After filling the formulations in the DPI devices, the devices areallowed to stand for at least 24 hours before testing.

The aerodynamic particle size distribution is determined using theAndersen Cascade Impactor Mark II, equipped with pre-separator and 8stages, designed and calibrated for 60 L/min flow rate (apparatus D ofthe Eur. Pharmacopoeia 4.4 section 2.9.18). The fine particle dose isthe amount of drug that is found on the stages 2 to the filter stage ofthis apparatus.

3 actuations of the formulations of Example 1 and 2 are discharged intothe particle sizing apparatus specified above by pulling 4 L of airthrough the apparatus at a set flow rate of 60 L/min. Delivered andaerosolised drug particles are classified in accordance with theirparticle momentum achieved in the flow which depends on the equivalentaerodynamic particle size. Thus fractions of the dose are deposited atdifferent parts or collecting stages of the apparatus, in accordancewith the aerodynamic particle size of the drug particles. Each fractionis collected, adjusted to volume and analysed using HPLC.

HPLC analysis of Formulation I showed that the fine particle fraction(less than 3.2 micrometers) of the dose delivered into the AndersenCascade Impactor apparatus is about 42%.

HPLC analysis of Formulation 3 showed that the fine particle fraction(less than 3.2 micrometers) of the dose delivered into the AndersenCascade Impactor apparatus is about 43%.

What is claimed is:
 1. A method of making a powder for inhalationconsisting of a first step (a) of mixing particles of aforce-controlling agent selected from magnesium stearate, with particlesof one or more pharmacologically active materials, wherein the mixing isachieved by one or more of the processes of sieving or blending, whereinthe blending is not carried out in a high shear mixer wherein the mixingresults in the particles of the force-controlling agent being disposedon the surface of the particles of the one or more pharmacologicallyactive materials as either a particulate coating or as a continuous ordiscontinuous film; and a second step of (b)(1) sieving or blending thepowder obtained in step (a) with 50-99 weight percent of a carriermaterial based on the total weight of the formulation, or (b)(2)blending the powder obtained in step (a) with a first portion of acarrier material to form a second mixture, and in a subsequent stepmixing the remainder of the carrier material with said second mixture,said carrier material having a particle size of 50-500 μm, wherein theparticles of one or more pharmacologically active materials compriseparticles of an anti-cholinergic drug in salt form selected from thegroup consisting of oxitropium bromide, glycopyrronium bromide,ipratropium bromide and tiotropium bromide.
 2. The method of claim 1,wherein the second step is step (b)(2), blending the powder obtained instep (a) with a first portion of a carrier material to form a secondmixture, and in a subsequent step mixing the remainder of the carriermaterial with said second mixture.
 3. The method of claim 1 or 2,wherein the blending is carried out in a diffusion blender, tumbleblender, bin blender, or conical blender.
 4. The method of claim 1,wherein the force-controlling agent is present in amounts of up to 5.0%by weight based on the total weight of the formulation.
 5. The method ofclaim 1, wherein the force-controlling agent is present in amounts of0.01 to 5.0% by weight based on the total weight of the formulation. 6.The method of claim 1, wherein the carrier material is selected fromglucose, lactose, lactose mono-hydrate, sucrose, trehalose, mannitol,xylitol, polylactic acid, or mixtures thereof.
 7. The method of claim 6,wherein the carrier material is lactose mono-hydrate.
 8. The method ofclaim 1, wherein the one or more pharmacologically active materials isselected from the group consisting of pharmacologically active materialshaving a contact angle against water that is less than 90°.
 9. Themethod of claim 1, wherein the one or more pharmacologically activematerials is selected from the group consisting of pharmacologicallyactive materials having an octanol-water partition coefficient (log P)smaller than 2.